Penicillin derivatives



United States Patent 3,280,111 PENICILLIN DERIVATIVES Emilio Testa,Vacalio, Tessin, Switzerland, and Giorgio Cignarella, Giorgio Pitieri,and Bruno J. R. Nicolaus, Milan, Italy, assignors to Lepetit S.p.A.,Milan, Italy No Drawing. Filed Apr. 2, 1962, Ser. No. 184,539 Claimspriority, application Great Britain, Apr. 14, 1961, 13,585/ 61 11Claims. (Cl. 260-2391) This invention relates to new penicillins derivedfrom 6-aminopenicillanic acid of the formula:

H2NCHCH C\ 0 ON-OHC 0 011 which possess high antibacterial activity andmay be used in treating both human and animal infections.

Some new penicillins have been prepared in recent years by acrylatingthe well known 6-aminopenicillanic acid, especially in view of someparticularly interesting properties, peculiar to a certain number ofthem, including that of being effective against penicillinase-producingstrains of bacteria.

This invention is more particularly concerned with the preparation ofnew penicillins of the general formula:

wherein R and R are the same or different members of the classconsisting of lower alkyl, aryl, aralkyl, X is a member of the classconsisting of halogen and acryloxy, and

non toxic salts thereof.

The non-toxic salts include non-toxic metallic salts, such as sodium orpotassium and non-toxic organic salts such as dibenzylethylenediamine(DED) saltsor the like, commonly used in the field of penicillins.

For instance organic bases which may be useful to this purpose aretri(lower)alkylamines, such as trimethylor triethylamine; procaine,dibenzylamine, N-benzyl-fi-phenethylamine, l-ephenamine,N,N-bis-dehydroabietylethylenediamine, N,N-dibenzylethylenediamine anddehydroabietylamine.

The process for preparing the new penicillins consists in reacting6-aminopenicillanic acid for a fermentation liquor containing it with anacrylating agent such as carboxylic acid halide or anhydride derivedfrom an u,a-disubstituted propionic acid of the following formula:

wherein R, R and X are as defined above, in the presence of an alkalimetal carbonate or bicarbonate or a tertiary amine base as aproton-acceptor, in an inert anhydrous organic solvent.

These acids are also new and are prepared starting from B-hydroxy-acidlactones by ring cleavage in alkaline medium and subsequent 'acrylation,when X is acryloxly, and in the case in which X is halogen, directly byring cleavage with the appropriate hydracid.

"ice

Staph. PV 43 Staph. PV 46 Inoculum size 2.10 6 2.10

Penicillin G a-Phenyl-a-isopropyl-Baeetoxyethylpenicillina-Phenyl-a-n-butyl-B-acetoxyethylpenicillina-Phenyl-a-benzyl-fi-aeetoxyethylpenieillin (DED salt)a-Phenyl-a-isopropyl-B-bromoethylpenicillin (K salt) a-Phe'yl-a-n-butyl-fl-bromoethylpenicillin (D E D salt)a-Phenyl-a-benzyl-B-bromoethylpenieillin (K salt) Moreover some of thenew penicillins show a high degree of stability towards acidic media.This property combined with the effectiveness described above againstpenicillinase producing strains of bacteria is the most importantfeature of these new penicillins.

It is known that the sensitivity of the conventional penicillins hasrepresented a great obstacle to the use of these antibioticsby oralroute. The discovery of penicillin V resolved partially this problem byallowing the oral administration, but still retaining the disadvantageof being ineffective against resistant strains of bacteria. Owing totheir stability both towards acids and penicillinase, the newpenicillins increase to a very great extent the possibilities of oraltherapy.

The resistance to acids is illustrated by the following table in which.the percent of non-afie-cted penicillin at dlfierent tunes in HCl N/ 10is given:

Time 0 15 30 1 min. min. min. hour Penicillin G (Na salt) 100 12.1 1. 73Penicillin V 100 89. 8 75. 4 a-Phenyl-a-ethyl-fi-bromoetliylpenicillin(DED salt) 100 76. 6 47. 6 a-Phenyl-wn-butyl-fl-aeetoxyethylpenieillin100 71. 1 54. 5 a-Phenyl-a-benzyl-B-aeetoxyethylpenicilliu (DED Salt)100 92. 0 80. l c m-Diphenyl-fl-bromoethylpenicillin (DED salt) 100 97.0 96. 5 a-Pheuyl-a-n-butyl-dbromoethylpenicillin (DED salt) 100 90. 283. 0 a-Phenyl-a-beuzyl-B-bromoethylpe cillin (K salt) 100 95.8 93.0a-Phenyl-a-isopropyl-fl-bromoethylpenioillin 100 70. 5 62. 1

The following non-limitative examples illustrate the invention.

EXAMPLE 1 a-Benzyl-a-phenyl-flaacetoxyethylpenicillin To 11.8 g. ofa-phenyl-u-benzyl-p-propiolactone dissolved in 200 ml. ethanol, 200 m1.of 10% NaOH are added, and the mixture is refluxed for 2 hours. Then theorganic solvent is removed in vacuo and the aqueous solution isacidified with 20% H 80 to give 13 g. ofa-benzyl-a-phenyl-B-hydroxypnopionic acid, M.P. 186- 190 C. Thirteengrams of a-benzyl-u phenyl-,8-hydroxypropionic acid are refluxed for 3hours in 40 ml. acetic anhydride. The excess acetic anhydride is removedin vacuo and to the oily residue 40 ml. SOCl are added. The mixture isrefluxed for 2 hours, then the thionyl chloride is removed in vacuo andthe oily residue distilled to give 11.7 g. ofot-phenyl-a-benzyl-flaacetoxypropionyl chloride, BJP. 155-160 C./O.8 mm.Hg.

To 18 g. of -6-arninopenicillanic acid dissolved in 200 ml. anhydrouschloroform, 39 ml. of triethylamine is added portionwise at roomtemperature and the mixture is kept under stirring for ten minutes. Then40 g. of a-phenyl-a-benzyl-/3-acetoxypropionyl chloride in 150 ml. ofanhydrous chloroform are added dropwise at 4 C. Stirring is continuedfor 1 hour at room temperature. The mixture is treated with N HCl enoughto reach pH 2.5. The organic phase is washed with water, dried over NaSO and the solvent removed in vacuo. The residue is taken up with etherand treated with potassium ot-ethylhexanoate. Yield 1.7 .g. of potassiuma-benzyl-wpheny1- fi-acetoxyethylpenicillin, M.P. 1 -115 C. Thedibenzylethylenediamine salt of the same melts at about 120 C.

EXAMPLE 2 a-Phenyl-a-isopropyl- -br0moethylpenicillin Into 150 ml. ofglacial acetic :acid a stream of gaseous hydrogen bromide is bubbled atroom temperature, lowering .at the end the temperature to 0.5 C. tocomplete saturation. Then a solution of 26.5 g. ofot-phenyhwisopropyl-propio-nolactone in 50 ml. of glacial acetic acid isadded dropwise with stirring. The mixture is allowed to stand for 2hours and then warmed at 80 C. for two hours. After cooling the aceticacid is distilled oif in vacuo, the residue is taken up with H O-diethylether, the organic phase washed until neutral to congo red, dried overNa SO and filtered. The solvent is removed and the oily residue treatedwith petroleum ether gives 25 g. of crystallineot-phenyl-a-isopropyl-fi-b-romopropionic acid, MAP. 1'04105 C.

To 23 g. of a-phenyl-a-isopropyl-fi-bromopropionic acid, 30 ml. ofthionyl chloride are added with stirring. The mixture is refluxed for 3hours. The excess thionyl chloride is removed and the residue distilledin vacuo to give 23 g. of ot-phenyl-u-isopropyl-B-bromopropionylchloride, B.P. 130-135 C./ 0.5 mm. Hg.

To 30 g. of =6-aminopenicillanic acid dissolved in 250 ml. of anhydrouschloroform, 39 ml. of triethylamine are added .at room temperature.Stirring is continued for 10 minutes, then the mixture is cooled to 0.4C. and a solution of 40 g. of a-phenyl-a-isopropyl-B-bromopropionylchloride in 150 ml. of anhydrous chloroform is added dropwise withstirring. At the end of the addition stirring is continued for 1 hour atroom temperature, then the solution is treated with N HCl enough toreach pH 2.5; the organic layer is washed with H 0 and dried over Na SOthe organic solvent is removed .in vacuo and the oily residue taken upwith anhydrous diethyl ether and treated with potassiumot-ethylhexanoate to give 43 g. of potassium orphenyl-u-isopropyl-fl-bromoethylpenicillin, M.P. 154160 C.

EXAMPLE 3 -ot-Phenyl-a-methyl-B-acetoxyethyl penici II in To a mixtureof 21.6 g. of 6-amin0penicillanic acid, 9.2 g. of sodium bicarbonate and600 ml. of H 0 cooled to 5 C., 26.4 g. of(-)-'0L-a.CCtOXYIIlCthYl-OC-PhBHYl-PI'O- pionyl chloride in 100 ml. ofacetone and 18 g. of NaHCO in 200 ml. of H 0 are-added dropwise withstirring. The mixture is allowed to stand for 1 hour at roomtemperature, then washed with diethyl ether; the aqueous phase is cooledto 0 C., adjusted to pH 2.5 with N HCl and extracted with diethyl ether.The ether solution is dried over Na' SO filtered, and adjusted to pH 7with an ether solution of dibenzylethylenediamine. Yield 49 g. ofdibenzylethylenediamine salt of(-)-ocphenyl-ot-methyl-B-acetoxyethylpenicillin, M.P. 86 C.

EXAMPLE 4 ot-Phenyl-a-n-butyl-fi-bromoethylpenicillin Into ml. ofglacial acetic acid a stream of gaseous anhydrous hydrogen bromide isbubbled at room temperature, saturation is completed at 0.5 C. Then 20.4g. of a-phenyl-ot-n-butyl-B-propionolactone dissolved in the minimumamount of acetic acid is added at 0 C. dropwise with stirring. Thetemperature rises to 1020 C. The mixture is allowed to stand 2 hours atroom temperature and then warmed at 80 C. for 2 hours. The organicsolvent is distilled off in vacuo and the oil residue is taken up withdiethyl ether; the organic solution is washed until neutral to Congored, dried over Na SO and filtered; the solvent is evaporated to give25.3 g. of a-phenyl-a-n-butyl-,B-bromopropionic acid; M.P. 100- 102 C.which, reacted with thionyl chloride, gives the corresponding acidchloride.

A solution of 17 g. of 6-aminopenicillanic acid in 200 ml. of anhydrouschloroform is treated with 24 g. of uphenyl-ot-n-butyl-fi-bromopropionylchloride in 100 ml. of anhydrous chloroform substantially as describedin Example 2. Ten grams of potassiuma-phenyl-a-n-butyl-fibromoethylpenicillin are obtained; M.P. 130 C. Thecorresponding dibenzylethylenediamine salt melts at 120- 123 C.

EXAMPLES 5-8 Following the same procedure as described in Examples 1 and3 the following penicillins were obtained:

The sodium salts are prepared by extracting with a solution of NaHCO theether solution of the penicillin until pH 6.5 is reached. The aqueoussolution is freezedried, the residue is taken up with anhydrous acetone,the inorganic salts are filtered and the solvent removed.

EXAMPLE 9 According to the procedure described in Examples 2 and 4 thefollowing penicillins are prepared:

., Yield,

percent We claim: 1. A member selected from the group consisting of theacids of the formula:

R S OH: 'o-ooNH oHofi o ylen diamine salt.

9. u,a-Diethyl-fi-chloroethylpenicillin dibenzylethylenediamine salt.

10. u-Phenyl 0c isopropyl-,8-bromoethy1penicillindibenzylethylenediamine salt. 7

11. A member of the group consisting of a penicillinu-Phenyl-a-butyLfl-bromoethylpenicillin dibenzyleth- 6 compound of theformula:

wherein X represents halogen.

References Cited by the Examiner UNITED STATES PATENTS 3,025,290 3/1962Doyle et a1 260-239.1 3,116,285 12/1963 Celmer et a1 260239.1 3,157,63911/1965 Doyle et a1 260239.1

FOREIGN PATENTS 880,042 10/ 1961 Great Britain. 900,666 7/ 1962 GreatBritain.

OTHER REFERENCES Hackhs Chemical Dictionary, page 21, second edition,1937.

Jour. Amer. Medical Assoc., page 466, May 24, 1958.

ALEX MAZEL, Primary Examiner.

NICHOLAS RIZZO, WALTER A. MODANCE, HENRY R. J ILES, J. W. ADAMS,Examiners.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF THE ACIDS OF THEFORMULA: